Recent examples of chimeric antigen receptor (CAR) T cell directed to solid tumors have been clinical (or even preclinical) failures. The invention described herein presents solutions for solid tumor and other oncology indications.
Cellular therapeutics that are introduced into cancer patients and traffic into tumor microenvironments encounter multiple barriers that limit their efficacy. These barriers include, but are not limited to: cellular anergy, intrinsic cell death, suboptimal cell trafficking, limited proliferation, limited effector function, poor “take” (survival, persistence and differentiation), active exclusion from tumors, persistent immunosuppression in the tumor microenvironment, and tumor-induced cell death. Almost all attempts to date to overcome these limitations require non-physiological manipulation of the cellular therapeutic both in vitro and in vivo. The efficacy of cellular therapeutics is therefore broadly hindered by both intrinsic and extrinsic factors.
Targeting solid tumors presents an additional set of challenges to overcome, for example, their overall lesser sensitivity to T cell mediated cytotoxicity, a microenvironment with differing immunosuppressive mechanisms between tumor types, and a lack of target antigens with favorable expression profiles. Additionally, solid tumors are heavily fortified against cellular therapeutic attack as they deploy an impenetrable extracellular matrix, hypoxia, and acidic pH. Despite the vast number of targets that have been investigated, only a small number are tumor-specific (e.g., expression is restricted to the tumor cell) and this finding, as such, illustrates the difficulty and the need to discover an effective solution for eliminating or reducing the tumor. Yet another problem for targeting tumors is the heterogeneity of the tumor cells which express different antigens and different levels of antigens. The invention described herein addresses these problems and provides additional benefits as well.